The chemopreventive potential of indole-3-carbinol, a naturally occurring phytochemical in cruciferous vegetables, has received much attention in light of its demonstrated in vivo efficacy to protect against chemical-induced carcinogenesis in animals. Moreover, the clinical benefits of indole-3-carbinol have also been demonstrated in human trials for cervical dysplasia, breast cancer, and vulvar intraepithelial neoplasia. Despite these advances in translational research, the mechanism by which indole-3-carbinol inhibits tumorigenesis remains inconclusive, which, in part, might be attributable to its metabolic instability and complicated pharmacological properties. The intrinsic instability of indole-3-carbinol in acidic milieu arises from the vinyl hemiaminal moiety of the indole ring. This unique structural feature underlies the high susceptibility of indole-3-carbinol to acid-catalyzed dehydration and condensation to generate a complicated series of oligomeric products in vivo, including DIM (3,3′-diindoylmethane), ICZ (indolo[3,2b]-carbazole), LTr1 (a linear trimer), CTr (a cyclic trimer), and CTet (a cyclic tetramer). Similar to indole-3-carbinol, all these metabolites exhibit inhibitory activities against tumor cell growth, albeit with moderate to low potency.
Mechanistic evidence indicates that indole-3-carbinol facilitates growth arrest and apoptosis by targeting a broad range of signaling pathways pertinent to cell cycle regulation and survival, including those mediated by Akt, NF-κB, Bcl-2, mitogen-activated protein (MAP) kinases, the cyclin-dependent kinase (CDK) inhibitors p21 and p27, and cyclin D1. However, as these signaling targets often operate in a cell-specific fashion, it remains in dispute whether any of them could solely account for the effect of indole-3-carbinol on growth arrest and apoptosis in tumor cells. Furthermore, indole-3-carbinol and its metabolites suffer from metabolic instability, unpredictable pharmacokinetic properties, and low in vitro antiproliferative potency, which render therapeutic concentrations difficult to predict in the body.
Recent years have witnessed the use of DIM as a scaffold to carry out structural modifications, which has led to three distinct antitumor agents with higher potency: (p-substituted phenyl)-DIMs (PPARγ agonists), SR13668 (an Akt inhibitor), and an indole-3-carbinol tetrameric derivative (a CDK6 inhibitor). These agents exhibit μM potency in inducing apoptosis or cell cycle arrest. However, they operate through signaling pathways distinct from those affected by DIM.
The use of indole-3-carbinol as a scaffold has previously been investigated as described in U.S. Patent Publication No. 2008/0300291 by Chen et al, the disclosure of which is incorporated herein by reference. In this previous work, Chen et al. described a series of pleiotropic anticancer agents that retained the broad spectrum antitumor activity of the parent compound while exhibiting enhanced metabolic stability and higher potency in various types of cancer. However, the need remains for additional antitumor compounds based on the indole-3-carbinol scaffold, and in particular for compounds exhibiting higher potency relative to previously identified compounds.